PDGF regulation of Mcl-1 expression in bone-metastatic human prostate cancer cells

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3583 Previous studies have shown that aberrant expression of platelet derived growth factor (PDGF) is correlated with human cancer progression. Overexpression of PDGF receptor (PDGFR) is implicated in the progression of prostate cancer (PCa) bone metastases. However, the role of PDGF signaling in prostate cancer cell growth and survival has not been well characterized. We studied the implication of PDGF signaling in an ARCaP human PCa progression model, which demonstrates epithelial to mesenchymal transition (EMT), and closely mimicking the clinical pathophysiology of human PCa bone metastasis. Treatment of metastatic ARCaPM cells with PDGFBB, an isoform of PDGF family, rapidly induced mRNA expression of myeloid cell leukemia-1 (Mcl-1), an antiapoptoic factor that has been correlated to higher Gleason grades and metastasis in clinical PCa specimens. Western blotting and reporter analyses confirmed PDGFBB as a novel regulator of Mcl-1 expression in PCa cells. Mechanistic study indicated that PDGF induction of Mcl-1 is mediated by a beta-catenin-dependent pathway. PDGFBB treatment induced rapid nuclear translocation of beta-catenin in ARCaPM cells. Further analyses suggested that beta-catenin signaling may be coupled with other transcriptional factors, i.e., cAMP-responsive element-binding protein (CREB) and T-cell factor 4 (TCF-4), to coordinately regulate Mcl-1 expression. Transient transfection of wild-type beta-catenin expression cDNA resulted in increased Mcl-1 expression, whereas a TCF-4 dominant negative cDNA effectively abrogated PDGFBB induction of Mcl-1 expression. In conclusion, these data demonstrate that activation of the PDGF-beta-catenin-Mcl-1 signaling may contribute to human PCa bone metastasis. Interruption of the Mcl-1 survival signal in addition to blocking the PDGF pathway may provide a novel target for the treatment of human PCa bone metastasis.